Natural products are a rich source of small molecules provided and inspired many drugs, particularly in the treatment of infectious diseases, cancers, hypercholesterolemia and immunological disorders. Cantharidin (1), in the form of the dried body of the Chinese blister beetles: Mylabris phalerata or M. cichorii, displays antitumor activity and induces apoptosis in many types of tumor cells. Cantharidin has been used as an anticancer agent by the Chinese for the treatment of hepatoma and esophageal carcinoma for a long time. Although cantharidin is a natural toxin that possesses potent anti-tumor properties, its clinical application is limited due to severe side-effects and highly toxic nature. Norcantharidin (2), the demethylated form of cantharidin has strong anticancer activity, and eliminates some side-effects in the urinary system, does not cause myelosuppression and increases the number of white blood cells. Although norcantharidin has improved activity and toxicity, the effects routinely do not satisfy the current clinical need. Exploring better analogues is vital for changing the current situation, but norcantharidin is a good lead compound.

Though numerous analogues of cantharidin and norcantharidin have been synthesized chemically and showed potential anticancer activities, there is little success on clinical application because of the potential toxicity of cantharidin and norcantharidin derivates. The present invention is to describe a method to synthesis of a type of novel norcantharidin analogues by transition metal-catalyzed alkynylation of 7-oxabenzonorbornadienes, and further discuss their bioactivities on tumour cells.
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